SARS-CoV-2 VOC type and biological sex affect molnupiravir efficacy in severe COVID-19 dwarf hamster model

DOI record: { "DOI": "10.1038/s41467-022-32045-1", "ISSN": [ "2041-1723" ], "URL": "http://dx.doi.org/10.1038/s41467-022-32045-1", "abstract": "<jats:title>Abstract</jats:title><jats:p>SARS-CoV-2 variants of concern (VOC) have triggered infection waves. Oral antivirals such as molnupiravir promise to improve disease management, but efficacy against VOC delta was questioned and potency against omicron is unknown. This study evaluates molnupiravir against VOC in human airway epithelium organoids, ferrets, and a lethal Roborovski dwarf hamster model of severe COVID-19-like lung injury. VOC were equally inhibited by molnupiravir in cells and organoids. Treatment reduced shedding in ferrets and prevented transmission. Pathogenicity in dwarf hamsters was VOC-dependent and highest for delta, gamma, and omicron. All molnupiravir-treated dwarf hamsters survived, showing reduction in lung virus load from one (delta) to four (gamma) orders of magnitude. Treatment effect size varied in individual dwarf hamsters infected with omicron and was significant in males, but not females. The dwarf hamster model recapitulates mixed efficacy of molnupiravir in human trials and alerts that benefit must be reassessed in vivo as VOC evolve.</jats:p>", "alternative-id": [ "32045" ], "article-number": "4416", "assertion": [ { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Received", "name": "received", "order": 1, "value": "1 March 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "Accepted", "name": "accepted", "order": 2, "value": "14 July 2022" }, { "group": { "label": "Article History", "name": "ArticleHistory" }, "label": "First Online", "name": "first_online", "order": 3, "value": "29 July 2022" }, { "group": { "label": "Competing interests", "name": "EthicsHeading" }, "name": "Ethics", "order": 1, "value": "M.G.N. and G.R.P. are coinventors on patent 20190022116, N⁴-Hydroxycytidine and derivatives and anti-viral uses related thereto, covering composition of matter and method of use of EIDD-2801 for antiviral therapy. This study could affect their personal financial status. All other authors declare no competing interests." } ], "author": [ { "affiliation": [], "family": "Lieber", "given": "Carolin M.", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0003-0620-1674", "affiliation": [], "authenticated-orcid": false, "family": "Cox", "given": "Robert M.", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-1660-1666", "affiliation": [], "authenticated-orcid": false, "family": "Sourimant", "given": "Julien", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-2507-6944", "affiliation": [], "authenticated-orcid": false, "family": "Wolf", "given": "Josef D.", "sequence": "additional" }, { "affiliation": [], "family": "Juergens", "given": "Kate", "sequence": "additional" }, { "affiliation": [], "family": "Phung", "given": "Quynh", "sequence": "additional" }, { "affiliation": [], "family": "Saindane", "given": "Manohar T.", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-8491-3824", "affiliation": [], "authenticated-orcid": false, "family": "Smith", "given": "Meghan K.", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-7022-1410", "affiliation": [], "authenticated-orcid": false, "family": "Sticher", "given": "Zachary M.", "sequence": "additional" }, { "affiliation": [], "family": "Kalykhalov", "given": "Alexander A.", "sequence": "additional" }, { "affiliation": [], "family": "Natchus", "given": "Michael G.", "sequence": "additional" }, { "affiliation": [], "family": "Painter", "given": "George R.", "sequence": "additional" }, { "affiliation": [], "family": "Sakamoto", "given": "Kaori", "sequence": "additional" }, { "affiliation": [], "family": "Greninger", "given": "Alexander L.", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-2034-2107", "affiliation": [], "authenticated-orcid": false, "family": "Plemper", "given": "Richard K.", "sequence": "additional" } ], "container-title": "Nature Communications", "container-title-short": "Nat Commun", "content-domain": { "crossmark-restriction": false, "domain": [ "link.springer.com" ] }, "created": { "date-parts": [ [ 2022, 7, 29 ] ], "date-time": "2022-07-29T19:04:06Z", "timestamp": 1659121446000 }, "deposited": { "date-parts": [ [ 2022, 7, 29 ] ], "date-time": "2022-07-29T19:07:19Z", "timestamp": 1659121639000 }, "funder": [ { "DOI": "10.13039/100000060", "award": [ "AI071002", "AI141222" ], "doi-asserted-by": "publisher", "name": "U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases" }, { "name": "U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases" } ], "indexed": { "date-parts": [ [ 2022, 7, 29 ] ], "date-time": "2022-07-29T19:41:53Z", "timestamp": 1659123713634 }, "is-referenced-by-count": 0, "issue": "1", "issued": { "date-parts": [ [ 2022, 7, 29 ] ] }, "journal-issue": { "issue": "1", "published-print": { "date-parts": [ [ 2022, 12 ] ] } }, "language": "en", "license": [ { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "tdm", "delay-in-days": 0, "start": { "date-parts": [ [ 2022, 7, 29 ] ], "date-time": "2022-07-29T00:00:00Z", "timestamp": 1659052800000 } }, { "URL": "https://creativecommons.org/licenses/by/4.0", "content-version": "vor", "delay-in-days": 0, "start": { "date-parts": [ [ 2022, 7, 29 ] ], "date-time": "2022-07-29T00:00:00Z", "timestamp": 1659052800000 } } ], "link": [ { "URL": "https://www.nature.com/articles/s41467-022-32045-1.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41467-022-32045-1", "content-type": "text/html", "content-version": "vor", "intended-application": "text-mining" }, { "URL": "https://www.nature.com/articles/s41467-022-32045-1.pdf", "content-type": "application/pdf", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "297", "original-title": [], "prefix": "10.1038", "published": { "date-parts": [ [ 2022, 7, 29 ] ] }, "published-online": { "date-parts": [ [ 2022, 7, 29 ] ] }, "published-print": { "date-parts": [ [ 2022, 12 ] ] }, "publisher": "Springer Science and Business Media LLC", "reference": [ { "key": "32045_CR1", "unstructured": "WHO. 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